Understand your Diagnosis

Inherited Metabolic Disorders (IMDs) is an umbrella term for the most important and vast group of rare and mostly recessively inherited genetic disorders due to an enzymatic block in a given biochemical pathway. Although individually rare, collectively IMDs are frequent with an estimated incidence ranging from 1/784 to 1/2500.

The term IMDs encompasses a diverse and heterogeneous collection of more than 800 genetic diseases, for this reason, considering the complexity of the IMDs field as a whole, the IMDS have been categorised in 7 different subgroups according to the specific disrupted metabolism.

Amino acid and organic acid diseases constitute the oldest group of inborn errors of metabolism. Some of them are universally adopted in the newborn screening and metabolic derangement can be prevented. Other disorders present as an overwhelming intoxication disorder leading to coma in a matter of hours. Some disorders are characterized by a peculiar smell or discoloration of the urine. These diseases are readily diagnosed in metabolic centers. In some specific diseases more targeted therapy with enzyme inhibitors or supplementation of specific vitamins can obviate the need for the complex diet. However, in most of these diseases a strict dietary therapy is necessary which often includes protein restriction. Large differences of available diet therapies exist between countries in the EU.

Disorders of pyruvate metabolism, mitochondrial oxidative disorders, thiamine transport and metabolism provide the essential fuel (ATP) for the functioning of the human cell. More than 300 genes are involved in normal mitochondrial function. The clinical presentation can be quite diverse ranging from eye disease to multisystem, neurologic and myopathic involvement. While this represents the most common inborn error in metabolism the severity can vary a lot from lethally affected newborns to monosymptomatic elderly. Diagnosis is certainly not straightforward as one mitochondrial disease can present with a multitude of symptoms and on the other hand, one symptom can be cause by many different mitochondrial diseases. Respiratory chain complexes (the important functional part of the mitochondrion) can be analysed by a few highly specialized laboratories across Europe. Treatment is often lacking, although numerous clinical trials have been launched.

Carbohydrate, fatty acid oxidation and ketone bodies diseases constitute a diverse group of inherited disorders playing a central role in the energy requirements of the cell. Most are characterized by hypoglycaemia in relation to food intake. Hypoglycaemia is one of the most common presentations of inborn errors of metabolism. Diagnostic work-up can be difficult and can require sampling at the time of a hypoglycaemia. In some disorders cardiomyopathy or myopathy is a central feature. Dietary therapy and avoidance of fasting plays an important role in preventing morbidity.

Lysosomal diseases constitute a group of over 50 inherited disorders in lysosomal metabolism.Most have multi-organ involvement, all are progressive and many have neurodegenerative features.Some can be treated, but for most only supportive care is available.The combined incidence is estimated at 1 new case per 5.000-10.000 newborns per year, which results in approximately 500 to 1000 new patients with a lysosomal disease in the EU per year.Diagnosis can be difficult as symptoms may slowly progress and highly specialized diagnostic tools are mandatory, often resulting in diagnostic delays. Large differences in awareness, availability of diagnostic tools and treatment options exist between countries in the EU.

Peroxisomal diseases and lipid related disorders constitute a growing group of inborn errors of metabolism. There clinical presentation of peroxisomal disorders can be quite diverse ranging from neurological and behavioural disease to bone abnormalities. Some are progressive and many have neurodegenerative features. For most of these diseases, treatment is largely supportive. The incidence of peroxisomal disorders is estimated at 1 new case per 20.000 newborns per year. Diagnosis can be difficult as symptoms may slowly progress and highly specialized diagnostic tools are mandatory, often resulting in diagnostic delays. Large differences in awareness, availability of diagnostic tools and treatment options exist between countries in the EU.

The lipid related disorders are a diverse group of inborn errors of metabolism. They include lipid synthesis and transport defects, and one of the most frequent groups of IMDs.

Congenital disorders of glycosylation diseases constitute a group of over 100 inherited disorders and every year new disorders are being discovered. Many proteins in the human body are glycosylated to be able to fulfil their function. Glycosylated proteins play a role in multiple biologic processes, and participate in cellular trafficking. Disorders of glycosylation often present with multisystem diseases. For some of these disorders dietary therapy with simple sugars can lead to great clinical improvements. Supportive care is paramount and care strategies vary broadly in Europe.

A neurological picture often including movement disorders, epilepsy and developmental delay mainly characterizes neurotransmitter and small molecule disorders diseases. Often invasive tests are required (for instance spinal fluid tap) to make the diagnosis and monitor therapy. Analysis of these samples is performed in a handful of specialized laboratories across Europe. Collaboration between neurologists and metabolic disease specialists is important to achieve optimal quality of life and symptom control. Vitamins can correct some of these disorders almost completely.

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